Multivariate analysis of prognostic factors in patients with lip squamous cell carcinoma after surgery

Background Lip squamous cell carcinoma (LSCC) was one of the most common cancer types of head and neck tumors. This study aimed to find more predictors of the prognosis in postoperative LSCC patients. Methods A total of 147 LSCC patients between June 2012 and June 2018 were collected from two tertiary care institutions. There were 21 clinicopathological factors included and analyzed in our study. The univariate and multivariate Cox regression analyses were performed to find the independent prognostic factors for predicting progression-free survival (PFS) and overall survival (OS) in postoperative LSCC patients. The role of adjuvant radiotherapy in various subgroups was displayed by Kaplan–Meier plots. Results The 1-, 3-, and 5-year PFS of postoperative LSCC patients were 88.4%, 70.1%, and 57.8%, respectively. Similarly, the 1-, 3-, and 5-year OS of postoperative LSCC patients were 94.6%, 76.9%, and 69.4%, respectively. The results suggested that postoperative LSCC patients with age at diagnosis ≥ 70 years, grade with moderate or poor differentiate, the American Joint Committee on Cancer (AJCC) stage IV, higher systemic immune-inflammation index (SII), surgical margin < 5, and age-adjusted Charlson Comorbidity Index (ACCI) ≥ 5 tend to have a poorer PFS (all P < 0.05). Besides, postoperative LSCC patients with age at diagnosis ≥ 70 years, AJCC stage IV, higher GPS, higher SII, and ACCI ≥ 5 tend to have a worse OS (all P < 0.05). Additionally, postoperative patients with LSCC in the subgroup of ACCI < 5 and AJCC III–IV stage was more likely to benefit from adjuvant radiotherapy, but not for the other subgroups. Conclusion We identified a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients by local data from two tertiary care institutions in China, which can be helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-024-03313-9.


Introduction
Lip squamous cell carcinoma (LSCC) is a type of oral cancer that accounts for about 25% of all oral cancer patients [1], and its incidence has shown a downward trend in recent years [2][3][4].The lip was the junction of oral squamous cells and skin squamous cells, and LSCC was the pathological and anatomical combination of oral mucosa squamous cell carcinoma and skin squamous cell carcinoma.The aggressiveness and prognosis of LSCC were intermediate between those of oral mucosa squamous cell carcinoma and head and neck skin squamous cell carcinoma [5].Smoking, long-term sunlight exposure, alcohol intake, and habitual chewing of betel nuts may be important acquired causes of lip cancer [6,7].Generally, the choice of treatment strategy and prognosis in LSCC patients depended on the traditional TNM AJCC stage.The tumor size, lymph node status, and distant metastasis are critical prognostic factors for those resected patients with LSCC, which has been reflected by the traditional TNM AJCC stage system.Surgery was still the main treatment for patients with LSCC [8,9].The prophylactic cervical lymph node dissection is the common method for estimating the lymph node status in LSCC patients.Besides, sentinel lymph node biopsy before surgical resection was another new method, which was mentioned in the notes of the Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for head and neck cancer (2018 version) [10] and has attracted the attention of many surgical experts, especially in patients with early-stage lip squamous cell carcinoma (LSCC) [11,12].However, due to the limitations of surgical techniques and other factors, the sentinel lymph node biopsy before surgical resection has not been commonly applied in all patients with early-stage lip squamous cell carcinoma (LSCC), especially in lowresource regions [13].Recently, more and more clinicians have found that LSCC patients with the same TNM AJCC stage had an entirely different prognosis and therapeutic schedule in practice.There are some other factors that also affect the prognosis and treatment choice of LSCC patients, such as the patient's general condition, immune status, nutritional status, and comorbidity.Therefore, it is important for us to find out more prognostic factors for LSCC patients, which can work as a complement to the traditional TNM AJCC stage system.
At present, there were risk factor analyses for the prognosis of patients with LSCC.These risk factors include age at diagnosis, marital status, sex, race, the American Joint Committee on Cancer (AJCC) stage, surgery status, positive lymph node ratio, total protein, immunoglobulin G, factor B, blood cell count, human papillomavirus (HPV) infection, and radiotherapy status [14][15][16].However, there were few studies on the prognostic factors of postoperative LSCC patients.Therefore, a retrospective study was designed to find more predictors of the prognosis in postoperative LSCC patients, which can provide a certain reference for clinical application.

Data collection
In this study, a total of 147 LSCC patients were obtained from the First Affiliated Hospital of Xinxiang Medical University and the Affiliated Cancer Hospital of Zhengzhou University between June 2012 and June 2018.The inclusion criteria were as follows: (1) pathology confirmed, (2) age at diagnosis ≥ 16, and (3) active follow-up.The exclusion criteria include the following: (1) There was distant metastasis at the time of initial diagnosis, (2) no radical resection was performed during the whole treatment, (3) patients who had received preoperative radiotherapy or preoperative chemotherapy, (4) dead within 30 days after surgery, (5) complete clinical data were not available, (6) patients who were lost to followup or did not cooperate with follow-up work, and (7) Eastern Cooperative Oncology Group performance status score (ECOG-PS) ≥ 3 before surgery.
We collected clinical data through the clinical case systems of the two medical institutions.A total of 21 clinicopathological variables of LSCC patients were included in the analysis, including age at diagnosis, gender, primary site, grade, AJCC stage, perineural invasion, vascular invasion, surgical margin, extranodal extension (ENE), adjuvant chemotherapy, adjuvant radiotherapy, ECOG-PS, Glasgow prognostic score (GPS), systemic immune-inflammation index(SII), prognostic nutrition index (PNI), platelet-to-lymphocyte ratio (PLR), ageadjusted Charlson Comorbidity Index (ACCI), neutrophil-to-lymphocyte ratio (NLR), hemoglobin, multiple primary tumors, and body mass index (BMI).The adjuvant chemotherapy in this study was platinum-based chemotherapy.The adjuvant radiotherapy was delivered by intensity-modulated radiotherapy (IMRT) with doses ranging from 50.0 to 71.0 Gy.A close margin was defined as a margin within 5 mm from the tumor.Overall survival (OS) and progression-free survival (PFS) were primary study endpoints.

Calculations
ACCI is a marker implicated in comorbidity and age status.The calculation method for ACCI is shown in Table S1.Besides, BMI, GPS, PLR, PNI, NLR, and SII are indicators related to inflammation and nutrition, and the calculation formulas for those indexes are displayed in Table S2.

Statistical analysis
All statistical analyses were performed by SPSS 20.0 software.Univariate Cox regression analysis was applied to find the potential predictors of OS and PFS.Then, these potential predictors were included for further analysis to reveal the independent predictors of OS and PFS by multivariate regression analysis.Additionally, all LSCC patients were divided into four subgroups based on the AJCC stage and ACCI to illustrate the benefit of adjuvant radiotherapy specifically (Table 4).Kaplan-Meier plots were used to display the benefit of adjuvant radiotherapy in these different subgroups.P < 0.05 was considered to be statistically significant.
There were 11 patients with multiple primary tumors: two patients had lung cancer, two had basal cell carcinoma, three had thyroid cancer, three had malignant lymphoma, and one had both oropharyngeal and breast cancer.2 and 3. Additionally, all enrolled postoperative patients with LSCC were divided into four subgroups according to the ACCI and AJCC stage, and the benefits of adjuvant radiotherapy on OS and PFS were displayed by the Kaplan-Meier plots in Table 4, Figs. 1 and 2. Obviously, there was a considerable benefit of prognosis in the subgroup of ACCI < 5 and AJCC stages III-IV for LSCC patients who receive adjuvant radiotherapy, but not for the other subgroups.

Discussion
LSCC was a common type of oral cancer.Mostly, the AJCC stage system was commonly applied to predict the prognosis of LSCC patients [1,17].Previously, various studies indicate that local advanced stage LSCC patients tend to have a poorer prognosis [18,19], which is consistent with our study.However, increasing studies suggest that other clinicopathological factors also had an important effect on the prognosis of LSCC patients except for the traditional AJCC stage system.
Age at diagnosis is a commonly used factor in assessing the general condition of cancer patients.There was a different morbidity and mortality in different age groups for most cancers.Wolfer S. et al. [20] showed that age at diagnosis had a different effect on prognosis depending on gender in oral cancer patients.However, some researchers suggest that age has little effect on prognosis or has an effect only in certain populations [21,22].It was controversial in the impact of age on the prognosis of LSCC patients.In this study, older patients with LSCC have shorter survival times, which was similar to the results of previous studies [14,18,23].
Tumor differentiation is a traditional clinical factor, which commonly have an important impact on the prognosis of patients with cancer to some extent.It has been always taken into account in the evaluation of prognosis and treatment choice in various cancers.Vesna Janevska et al. [24] found that poorer differentiation can increase the density of neoangiogenesis in lower LSCC patients.In this study, we found that LSCC patients with moderate or poor differentiate tend to have a relatively worse PFS in comparison to LSCC patients with well differentiate, which is consistent with previous studies.As is well known, OS is more likely to be affected by multiple clinical or social factors than PFS.Therefore, it is reasonable that tumor differentiation is not an important factor for predicting OS of LSCC patients according to our results.Although the definition of "close margin" has always been a controversial topic in oral cancer surgery, there is a consensus that close margin may improve local recurrence rate and reduce long-term survival [25][26][27][28].Our study suggested that a surgical margin distance within 5 mm from the tumor is unsafe and will predict a poor prognosis.Due to the delicate anatomical structure of the maxillofacial region, excessive surgical margins may destroy organ function and cause cosmetic defects.Further studies with a larger sample size were needed to determine the appropriate surgical margins.
Previous researchers had paid their attention to ENE and vascular invasion in oral cancer [3,[17][18][19][20].In our study, although ENE and vascular invasion were not the independent prognostic factors, they had significantly negative effects on both OS and PFS in postoperative LSCC patients by univariate Cox analysis.If the pathological and imaging results show ENE and/or vascular invasion, the clinicians should adjust the treatment intensity and follow-up frequency.
As we all know, inflammation-related indicators generally play an important role in tumor microenvironment and treatment [29][30][31][32].Complete blood count (FBC), C-reactive protein (CRP), and albumin can reflect the systemic inflammatory status of cancer patients and thus predict prognosis to some extent [29,33].SII, GPS, and PNI are indicators of systemic inflammation status calculated from the above clinical data, reflecting not only systemic inflammation but also the antitumor response  and immune monitoring status of the patient.Increased neutrophil counts or neutrophilia in cancer occur due to the secretion of myeloid growth factors by tumor cells triggering neutrophil production or due to cancer-related inflammation secondary to tissue destruction or hypercytokinemia [34].Lymphocytopenia and neutropenia are often associated with reduced antitumor response and immunosuppression [29,[35][36][37].Numerous studies have revealed a negative correlation between SII and tumor prognosis [38][39][40][41][42].Both GPS and PNI incorporate serum albumin levels, which reflect a patient's nutritional, immune, and inflammatory status, and were all important prognostic factors [43][44][45][46][47].However, the effects of SII, PNI, and GPS on the prognosis of LSCC had not been studied.In our study, higher SII was independent predictors of PFS and OS.Besides, the higher the GPS, the worse the OS in LSCC patients according to the results.PNI has some effects on the prognosis of LSCC patients, but was not the independent predictors of prognosis.All these results were an important supplement to the study of LSCC.
The ACCI is a useful comorbidity indicator, which is commonly utilized to normalize the assessment of patients of different ages and has been reported to predict the mortality of various cancers [48][49][50].In our study, for LSCC patients who underwent adjuvant radiotherapy, the OS (P = 0.016) and PFS (P = 0.018) were significantly improved in subgroup of AJCC stages III-IV and ACCI < 5.Moreover, in the subgroup of ACCI ≥ 5 or AJCC stages I-II, adjuvant radiotherapy did not have any benefit in improving the prognosis.Therefore, it is importantly that we should not only refer to the AJCC stage system but also pay more attention to patients' ACCI scores in choosing the optimal treatment strategy for postoperative LSCC patients.There are also some limitations in our study.Firstly, this was a retrospective study, which had some inevitable selective bias.Secondly, due to the low incidence of LSCC, the selected cases were small and cannot reflect the situation of all LSCC patients in China.Finally, some potential prognostic factors were not included in the analysis, such as pain score, tumor markers, dietary habits, marital status, and preoperative mean platelet volume.Further research should be conducted to find more prognostic factors in LSCC patients.

Conclusion
In summary, a series of significant immune-inflammation-related and comorbidity-related clinicopathological factors associated with the prognosis of postoperative LSCC patients were identified in this study.It is helpful for patients and surgeons to pay more attention to nutrition, inflammation, and complications and finally obtained a better prognosis.

Fig. 1
Fig. 1 The effects of adjuvant radiotherapy on OS in different subgroups by Kaplan-Meier curves.A AJCC stages I-II and ACCI 2-4.B AJCC stages III-IV and ACCI 2-4.C AJCC stages I-II and ACCI ≥ 5. D AJCC stages III-IV and ACCI ≥ 5. ACCI, age-adjusted Charlson Comorbidity Index; OS, overall survival

Fig. 2
Fig. 2 The effects of adjuvant radiotherapy on PFS in different subgroups by Kaplan-Meier curves.A AJCC stages I-II and ACCI 2-4.B AJCC stages III-IV and ACCI 2-4.C AJCC stages I-II and ACCI ≥ 5. D AJCC stages III-IV and ACCI ≥ 5. ACCI, age-adjusted Charlson comorbidity index; PFS, progression-free survival

Table 1
Clinicopathological characteristics of postoperative LSCC patientsAbbreviations: ACCI age-adjusted Charlson comorbidity index, AJCC American Joint Committee on Cancer, BMI body mass index, ECOG-PS, Eastern Cooperative Oncology Group performance status score, ENE extranodal extension, GPS Glasgow prognostic score, IQR inter-quartile range, LSCC, lip squamous cell carcinoma, NLR neutrophil-to-lymphocyte ratio, OS overall survival, PFS progress-free survival, PLR platelet-to-lymphocyte ratio, PNI prognostic nutrition index, SII systemic immune-inflammation index

Table 2
(continued) ACCI age-adjusted Charlson comorbidity index, AJCC American Joint Committee on Cancer, BMI body mass index, CI confidential interval, ECOG-PS Eastern Cooperative Oncology Group performance status score, ENE extranodal extension, GPS Glasgow prognostic score, HR hazard ratio, LSCC lip squamous cell carcinoma, NLR neutrophil-to-lymphocyte ratio, PFS progression-free survival, PLR platelet-to-lymphocyte ratio, PNI prognostic nutrition index, SII systemic immune- Abbreviations:

Table 3
Univariate and multivariate analyses results for OS in postoperative LSCC patients

Table 3
(continued) ACCI age-adjusted Charlson comorbidity index, AJCC American Joint Committee on Cancer, BMI body mass index, CI confidential interval, ECOG-PS Eastern Cooperative Oncology Group performance status score, ENE extranodal extension, GPS Glasgow prognostic score, HR hazard ratio, LSCC lip squamous cell carcinoma, NLR neutrophil-to-lymphocyte ratio, OS overall survival, PLR platelet-to-lymphocyte ratio, PNI prognostic nutrition index, SII systemic immune- Abbreviations:

Table 4
Impact of adjuvant radiotherapy on PFS and OS in different subgroups of postoperative LSCC patients Abbreviations: ACCI age-adjusted Charlson comorbidity index, AJCC American Joint Committee on Cancer, LSCC lip squamous cell carcinoma, PFS progression-